Alkanoylnaphthyloxy-carboxylic acids



United States Patent 3 352 988 ALKANOYLNAPHTHY LOF KY-CARBGXYLIC ACIDSWilliam A. Bolhofer, Frederick, and John J. Baldwin,

Lansdale, Pa, assignors to Merck & Co., Inc., Rahway,

NJ a corporation of New Jersey N0 Drawing. Filed Aug. 19, 1964, Ser. No.390,729 11 Claims. (Cl. 260-520) This application is acontinuation-in-part of application Ser. No, 302,484, filed Aug. 15,1963, now US. Patent No. 3,255,242 and also a continuation-in-part ofapplication Ser. No. 152,137, filed Nov. 14, 1961, now abandoned.

This invention relates to a new class of alkanoyl substitutednaphthyloxy-carboxylic acids, compounds which exhibit good diureticactivity and which are also useful as chemical intermediates in thepreparation of other pharmacologically active products.

Pharmacological studies show that the products of this invention areeffective diuretic and saluretic agents and are thus useful in therapyfor the treatment of conditions resulting from an excessive retention ofelectrolytes or fluid within the body as, for example, in the treatmentof hypertension, edema and other conditions associated with electroylteand fluid retention. Furthermore, the products of this invention reactwith the salts of secondary amines in the presence of formaldehyde orparaformaldehyde to produce Mannich amines and the amine salts thusprepared may be treated with a weak base to produce (2-methylenealkanoyl)naphthyloxy-carboxylic acids. The 2- methylenederivatives thus formed also have utility as diuretic and salureticagents and thus may also be used in the treatment of conditionsassociated with electrolyte and fluid retention.

The products of the invention are compounds having the followingstructural formula:

wherein m is an integer having a value of 1-3 as, for example,1,4-methylenephenyl, 1,3-methylenephenyl, etc., and arylene, forexample, a mononuclear arylene such as phenylene, etc.; R is a memberselected from the group consisting of'an alkyl radical containing fromone to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl,butyl, isobut'yl, enanthyl, etc., trihalomethyl sub stituted alkyl, forexample, trifluoromethyl substituted lower alkyl such asl-(trifluoromethyl)ethyl, 2,2,2-trifiuoroethyl, etc., cycloalkyl, forexample, mononuclear lower cycloalkyl containing from five to about sixnuclear carbon atoms such as cyclopentyl, cyclohexyl,4-methylcyclohexyl, etc., aralkyl, for example, mononuclear loweraralkyl such as benzyl', phenylethyl, etc., aryloxy, for example,mononuclear aryloxy such as phenoxy, naphthoxy, etc., arylthioalkyl, forexample, mononuclear arylthio-lower alkyl such as phenylthiomethyl,phenylthioethyl, etc.,

3,362,938 Patented Jan. 9, 1968 aralkylthio, for example, mononuclearlower aralkylthio such as benzylthio, phenethylthio, etc. andcarboxyalkyl, for example, carboxy-lower alkyl such as carboxymethyl,Z-carboxyethyl, 3-carboxypropyl, etc.; R and R each represents a memberselected from the group consisting of hydrogen, lower alkyl, forexample, methyl, ethyl, propyl, etc., and, taken together, the R and Rradicals may be joined to form a cycloalkyl ring containing from five tosix nuclear carbon atoms, for example, cyclopentyl, cyclohexyl, etc.; Xis a member selected from the group consisting of hydroxy, lower alkoxy,for example, methoxy, ethoxy, propoxy, etc., and amido, for example, anamido radical of the formula mula: V

Ii g I? CT TO CnH2u GOH wherein R is lower alkyl; X is a member selectedfrom the group consisting of hydrogen, halogen and lower alkyl; and n isan integer having a value of 1-5. The above class of compounds exhibitparticularly good diuretic activity and represent a preferred subgroupof compounds within the scope of this invention.

This invention also relates to the acid addition salts of the instantcarboxylic acids, which are prepared by the reaction of the said acidswith a base having a non-toxic, pharmacologically acceptable cation. Ingeneral, any base which will form an acid addition salt with the instantcarboxylic acids and whose pharmacological properties will not cause anadverse physiological eifect when ingested by the body system isconsidered as being within the scope of this invention; suitable basesthus include, for example, the alkali metal and alkaline earth metalhydroxides, carbonates, etc., ammonia, primary, secondary and tertiaryamines, such as monoalkylamines, dialkylamines, trialkylamines, nitrogencontaining heterocyclic amines, e.g., piperidine, etc. The acid additionsalts thus produced are the functional equivalent of the correspondingacid and one skilled in the art will appreciate that to the extent thatthe carboxylic acids of the invention are useful in therapy the varietyof said acid addition salts is limited only by the criterion that thebases employed in forming the said salts be both non-toxic andphysiologically acceptable.

The products of the invention may be prepared by any one of a variety ofdifferent methods. One method which has proved to be particularlysuitable comprises the reaction of an alkanoyl substituted naphthol(III, infra) with an halo substituted carboxylic acid ester, followed bythe hydrolysis of the carboxylate intermediate (11, infra) thus formedto the desired alkanoyl-naphthyloxy-carboxylic acid (I). The reaction ofthe naphthol with the halo-carboxylate is conducted in the presence of abasic reagent as, for example, in the presence of an alkali metalalkoxide, alkali metal carbonate or sodium and, generally, a solventsuch as a lower alkanol or N,N-dimethylformamide is employed. Suitablebasic reagents which may be used in the process include, for example,sodium methoxide, sodium ethoxide, potassium carbonate, sodium hydride,etc. The reaction is illustrated by the following equation:

wherein the radicals B, R, R R X and X are as defined above, Xrepresents an hydrocarbyl group (i.e., a monovalent organic radicalcomposed solely of carbon and hydrogen) such as lower alkyl, forexample, methyl, ethyl, propyl, etc. and X is halogen, for example,chlorine, bromine, iodine, etc. The saponification step in the aboveequation is conducted in a conventional manner as, for example, bytreatment of the carboxylate intermediate (II) with-a base, such as anaqueous solution of an alkali metal hydroxide, e.g., sodium hydroxide,potassium hydroxide, etc., and then with an acid, e.g., hydrochloricacid, to produce the corresponding carboxylic acid (I).

The hydroxy substituted alkanonaphthone starting materials, identifiedin the above equation as compound III, are conveniently prepared bymethods well-known to those having ordinary skill in the art. Thus, anaphthol, or an appropriately substituted derivative thereof, may beacylated by conventional means to produce the desired acylatcdderivative or, alternatively, an alkoxy-naphthalene compound may beemployed as the precursor in an otherwise similar process and thealkoxy-alkanonaphthone thus produced may be converted to the desiredhydroxy compound (III).

Specifically, one method for the preparation of thehydroxy-alkanonaphthone compounds (III) comprises treating a naphtholwith an alkanoyl halide to produce the corresponding naphthol ester. Theester derivative thus produced is then heated in the presence ofaluminum chloride according to the Fries Reaction and a nuclearrearrangement is effected which produces the desiredhydroxyalkanonaphthone (III).

Another method for preparing the hydroxy-alkanonaphthone compounds (III)comprises the reaction of an alkoxy substituted naphthalene with anappropriate alkanoic acid in the presence of boron trifluoride, followedby cleavage of the alkoxy group in the alkoxy substitutedalkanonaphthone intermediate thus produced. Agents which are'suita-blefor converting the alkoxy substituted alkanonaphthone intermediate tothe desired hydroxyalkanonaphthone (III) include, for example, pyridinehydrochloride, aluminum chloride and alkyl-magnesium all halide, andthese are advantageously employed with heating and in the presence of aninert gas.

Still another route for preparing the hydroxy-alkanonaphthone compounds(III) relates to the Friedel-Crafts method of synthesis. Thus, an alkoxysubstituted naphthalene compound is reacted with an appropriate alkanoicacid halide in the presence of anhydrous aluminum chloride, preferablyin a solvent as, for example, in nitrobenzene, carbon disulfide, hexane,benzene or methylene chloride, to yield the corresponding nuclear alkoxysubstituted alkanonaphthone and the alkoxy substituted intermediate thusformed is then cleaved by the method described in the precedingparagraph to produce the desired hydroxy-alkanonaphthone (III).

A modification of the foregoing Friedel-Crafts synthesis comprisestreating an acetamido substituted naphthalene compound with alkanoicacid halide in the presence of anhydrous aluminum chloride, followed byacid hydrolysis of the acetamido-alkanonaphthone thus formed to thecorresponding amine derivative and diazotization of the said amine withan aqueous sodium nitrite or nitrous acid ammonium chloride solution andconversion of the a1 koxy substituted alkanonaphthone thus obtained tothe desired hydroxy analog (III) as, for example, by treatment of thesaid alkoxy derivative with pyridine hydrochloride or with any of theother aforementioned reagents suitable for converting the alkoxyintermediates to their hydroxy derivatives (III).

Still another method for preparing the hydroxyalkanonaphthones (IH)comprises the treatment of a methoxy substituted halonaphthalene with asuspension of magnesium metal and iodine in an inert solvent, followedby the reaction of the complex thus formed with an appropriatealkylnitrile; the imino intermediate thus prepared is then hydrolyzed inan aqueous ammonium chloride solution to its alkoxy-alkanonaphthone andthe said alkoxy derivative is converted to the desired hydroxyderivative (III) by conventional means. Alternatively, thenaphthalene-Grignard complex, prepared as described above, may bereacted with an appropriate alkanal to produce an alpha-hydroxysubstituted alkyl-naphthalene and the hydroxy derivative thus preparedis oxidized by treatment with a pyridine-chromium trioxide reagent toproduce the desired alkoxy-alkanonaphthone which can then be convertedto the desired hydroxy analog (III) by the method described above.

Finally, when the hydroxy-alkanonaphthone (IH). is an8-hydroxy-l-alkanonaphthone or a 3-hydroxy-2-alkanonaphthone, the saidstarting material is prepared by the condensation of an appropriatelysubstituted alkoxynaphthoic acid, such as an 8-methoxy-1-naphthoic acidor 3-methoxy-l-naphthoic acid, with thionyl chloride; the naphthoylchloride thus produced is then treated with a cadmium alkyl in asuitable solvent (e.g., in benzene), subjected to reflux for a shortinterval and treated with a dilute aqueous solution of sulfuric acid toyield the corresponding 8-methoxy-l-alkanonaphthone or 3-me'thoxy-l-alkanonaphthone derivative. The methoxy derivative thus producedis then converted by conventional means as, for example, by treatmentwith aluminum chloride or by treatment with boron tribromide to producethe desired hydroxy substituted l-alkanonaphthone.

A second method for preparing the alkanoyl substituted naphthyloxycarboxylic acids (I) of this invention comprises treating anaphthyloxy-carboxylic acid of the Formula IV, infra, with a suitableacid halide in the presence of a metallic halide according to theFriedel- Crafts method of synthesis. The following equation illustratesthe reaction! wherein the radicals B, R, R R X X and X are as definedabove and MX represents a metallic halide. The metallic halides act ascatalysts in the condensation of the acid halide with thenaphthyloxy-carboxylic acid compound (IV) and include, for example,anhydrous aluminum chloride and boron trifluoride. The reaction solventand the temperature at which the condensation is conducted are notparticularly critical inasmuch as any solvent which is inert to the acidhalide and naphthyloxycarboxylic acid reactants and the metallic halidecatalyst may be employed with good results and the reaction temperaturemay be varied to obtain the desired rate of reaction. However, carbondisulfide is a particularly suitable solvent in which to conduct thereaction and, generally, it is most desirable to conduct the synthesiswith slight heating as, for example, at reflux temperatures by heatingon a steam bath.

Those arylalkanoyl substituted naphthyloxy-car-boxylic acidscorresponding to Formula I, supra, wherein R represents aralkyl, areconveniently prepared by the condensation of an alkanoyl substitutednaphthyloxy-carboXylic acid, having the Formula V, infra, with anaraldehyde followed by hydrogenation of thearylacryloylnaphthyloxy-carboxylic acid (VI) thus produced to thedesired product (I). The following equation, wherein the araldehyde isbenzaldehyde, illustrates the process; other araldehydes such asa-phenylacetaldehyde, etc. may also be employed in a similar manner toobtain the desired aralkyl substituted product:

wherein the radicals B, R X and X are as defined above. Hydrogenation inthe presence of palladium on charcoal and in the presence of an alcohol,such as isopropyl alcohol, is a particularly advantageous method by fiwhich to reduce the alkylidene group of compound VI to its correspondingphenylalkanoyl analog (I). However, any one of variety of otherreductants well-known to those skilled in the art may also be employedin a similar manner to achieve the desired result.

The oxy and thio substituted alkanoyl-naphthyloxycarboxylic acidproducts corresponding to Formula 1, supra, wherein R represents anaryloxy, an arylthioalkyl or an aralkylthio radical are prepared bytreating an haloalkanoyl-naphthyloxy-carboxylic acid with an appropriatephenol, naphthol, thiophenol, benzylmercaptan, etc., in the presence ofa base as, for example, in the presence of an aqueous solution ofpotassium hydroxide or sodium hydroxide. Generally, the reaction may beconducted in any suitable inert solvent but preferably an alcoholicmedium such as methanol, ethanol, etc., is employed. Thehaloalkanoyl-naphthyloxy-carboxylic acids employed as reactants in theprocess are prepared by any one of several methods but one route whichhas proved particularly advantageous is the Friedel-Crafts reaction of anaphthyloxy-carboxylic acid with an appropriate halo substitutedalkanoyl halide, for example, an omega-chlorobutyryl chloride,chloroacetyl chloride, etc., in the presence of. anhydrous aluminumchloride.

The presence of a lower alkyl substituent at the 5 position of thenaphthol (III) or naphthyloxy-carboxylic acid (IV) reactant makes itextremely difiicult to prepare the S-alkyl substituted products of thisinvention by either of the aforementioned etherification or acylation(i.e., Friedel-Crafts) processes. Therefore, We have found it necessaryto produce the said 5-alkyl derivatives by a circuitous route whichinvolves the use of dihydro and tetrahydro derivatives of naphthaleneand aromatization of the polyhydro derivatives thus employed to theircorresponding naphthalene analogs. Specifically, this method ofpreparation comprises the reaction of an alkanoyloxy-3,4-dihydro-1(2H)-napthalenone with magnesium and an alkyl iodide toproduce an l-hydroxy-l-alkyl-l,2,3,4- tetrahydro-S-naphthol followed byetherification of the said naphthol by treatment with an alkylhaloalkanoate in the presence of an alkali metal alkoxide to produce thecorresponding alkyl(S-hydroxy-S-alkyl-S,6,7,8-tetrahydro-l-naphthyloxy)alkanoate; thealkanoate derivative thus formed is then dehydrated to the correspondingalkyl (7,8-dihydro-5-alkyl-l-naphthyloxy)alkanoate, hydrogenated to itsalkyl (5,6,7,8-tetrahydro-5-alkyl-lnaphthyloxy)alkanoate derivative,saponified to produce the corresponding alkanoic acid and then treatedwith an alkanoyl-halide to yield a 4 alkanoyl-5-alkyl-5,6,7,8-tetrahydro-l-naphthyloxy alkanoic acid; the said acid is then esterifiedby conventional means, aromatized with a suitable reagent as, forexample, with 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone in benzene and,if desired, saponified to its corresponding carboxylic acid by treatmentwith an aqueous solution of hydrochloric acid.

The ester and amide derivatives of the instant alkanoyl substitutednaphthyloxy-carboxylic acids ('1) are prepared by conventional methodsWell-known to those skilled in the art; thus, for example, the saidester derivatives may be prepared by the reaction of the acid productsof the invention with an alcohol as, for example, with a lower alkanolto prepare the corresponding ester or, alternatively, converting thecarboxylic acid product to its acid halide by conventional methods andtreating the acid halide thus formed with an appropriate lower alkanol.Similarly, the amide derivatives of the instant carboxylic acid products(I) may be prepared by treating an acid halide of the instant acids withammonia or an appropriate alkylamine or dialkylamine to produce thecorresponding amide. The ester derivatives of the alkanoic acids of theinvention may also be prepared inherently during the process byemploying the ester analogs of the corresponding haloalkanoic acidreactants described in the preparative method discussed above. These andother equivalent methods for the preparation of the ester and amidederivatives of the instant carboxylic acids will be apparent to onehaving ordinary skill in the art and, to the extent that the saidderivatives are both non-toxic and physiologically acceptable to thebody system, the said esters and amides are the functional equivalent ofthe corresponding carboxylic acids per se.

The alkanoyl substituted naphthyloxycarboxylic acids of the inventionare generally obtained as crystalline solids and, if desired, may bepurified by recrystallization from a solvent. Suitable solvents include,for example, ethanol, isopropyl alcohol, cyclohexane, hexane, benzeneand mixtures thereof such as a mixture of ethanol in water, benzene incyclohexane, benzene and hexane, benzene and methanol and isopropylalcohol and water.

The products of the invention exhibit diuretic, natriuretic andchloruretic properties and, therefore, are useful as pharmaceuticals inthe treatment of ailments resultingfrom an excessive retention ofelectrolytes in the body, especially sodium, chloride or sodium andchloride ions.

In addition, the products of the invention are highly valuable chemicalintermediates which may be converted to their corresponding(2-methylenealkanoyl)-naphthyloxy-carboxylic acid compounds by themethod described in copending application Ser. No. 302,484 filed Aug.15, 1963, of which the instant application is a continuationinap-art.The said (2-methylenealkanoyl)-napthyloxycarboxylic acids are alsouseful as diuretic and saluretic agents and are characterized by a rapidand marked removal of electrolyte with no danger of excessiveelectrolyte depletion.

The examples which follow illustrate the method of preparing thealkanoyl substituted naphthyloxy-carboxylic acids of the invention aswell as the intermediates necessary to their preparation. However, theexamples are illustrative only and it will be apparent to one havingordinary skill that all of the products embraced by Formula I, supra,may also be prepared in an analogous manner by substituting theappropriate starting materials for those set forth in the examples.

EXAMPLE 1 (5-batyryl-I-naphthyloxy)acetic acid STEPA.-5-METHOXY-l-NAPHTHONITRILE To a well-stirred solution of 48.2 g.(0.285 mole) of S-hydroxy-l-naphthonitrile in 250 ml. of 2 N potassiumhydroxide, there is added 26.5 ml. (0.285 mole) of methyl sulfate over aone-minute period. A warming effect is observed and solid product beginsto separate. After 5 minutes, additional methyl sulfate (13.3 ml., 0.142mole) is added, the mixture becomes acidic and additional 2 N potassiumhydroxide is added to maintain alkalinity. After 15 minutes the solidproduct is collected, washed with water and dried. The crystallineproduct is dissolved in 550 ml. of hot isopropyl ether, the solutionfiltered and then concentrated to 200 ml. After crystallization at C.,30.0 g. of S-methoxy-l-naphthonitrile is collected, M.P. 87-89 C.

Analysis for: C H NO.--Calculated: C, 78.67; H, 4.95; N, 7.65. Found: C,78.52; H, 4.72; N, 7.85.

STEP B.--METHOXY-1-BUTYRONAPHTHONE A Grignard reagent is prepared from0.248 mole of magnesium and 0.248 mole of n-propyl bromide in 325 ml. ofether. To the vigorously stirred, refluxing solution of the Grignardreagent, a solution of 41.2 g. (0.225 mole) ofS-methoxy-l-naphthonitrile in 450 ml. of ether is added over a tenminute period. The reflux condenser is changed for downward distillationand 550 ml. of toluene is added at a rate equal to that of the etherbeing removed by distillation. After all the toluene has been added,distillation is continued until the vapor temperature reached 109 C. Thedownward condenser is replaced by an upright condenser and refluxingcontinued for four hours. The mixture is cooled to room temperature and250 ml. of saturated ammonium chloride solution added. The toluene phaseis separated and the aqueous phase extracted with ether which is thencombined with the toluene. The combined solvent extracts are extractedwith 400 and 200 ml. portions of 1 N sulfuric acid. The acid extractsare combined and allowed to stand at 20 C. After 18 hours, crystallineS-methoxy 1 butyronaphthone is collected, washed with water and dried,yield 46.0 g. After recrystallization from isopropyl ether, the productmelts at 67 69 C.

Analysis for: C H O .-Calculated: C, 78.92; H, 7.06. Found: C, 78.87; H,7.00.

STEP C.-5-HYDROXY-1-BUTYRONAPHTHONE ture of ml. of 1 N hydrochloric acidand 100 ml.

of ether. The ether layer is separated, extracted with water and thenthe naphthol is extracted into 75 ml. of 1 N sodium hydroxide. Dissolvedether is removed from the alkaline solution by bubbling a stream ofnitrogen through it. A limited amount of 1 N hydrochloric acid is addedto precipitate the tarry by-products. The mixture then is filtered, thefiltrate acidified and the solid material collected and washed withwater, yielding 7.4 g. of crystalline 5-hydroxy-l-butyronaphthone, M.P.8385 C. After recrystallization from a mixture of benzene and hexane theproduct melts at 8486 C.

7 Analysis for: C H O .Calculated: C, 78.48; H, 6.59. Found: C, 78.76;H, 6.68.

STEP D.(5-BUTYRYL-1-NAPHTHYLOXY)ACETIC ACID S-hydroxy-lrbutyronaphthone(17.7 g., 0.0825 mole) is added to a solution of 0.0867 mole of sodiumethoxide in 250 ml. of ethyl alcohol. A dark solution results, to whichis added 16.6 g. (0.099 mole) of ethyl bromoacetate. The solution isheated under reflux for three hours and then .ml. of 1 N sodiumhydroxide is added.

'Refluxing is continued for 20 minutes and then the ethyl EXAMPLE 2Ethyl (4-isovalayl-1 -naphthy l0xy acetate STEPA.-4-\IETHOXY-1-ISOVALERONAPHTHONE A solution of 158 g. (1 mole) ofl-methoxynaphthalene and 204 g. (2 moles) of isovaleric acid at 0 C. issaturated with boron trifluoride. The dark red mixture then is heated to75 C. and maintained at that temperature for 6 hours, the reactionmixture then is poured onto a mixture of 500 g. of ice, 500 g. of waterand 500 g. of sodium acetate whereupon an oil separates and is extractedwith ether. The ethereal extract is dried over sodium sulfate and thesolvent removed. The residue is distilled under reduced pressure, thedistillate solidifies and is recrystallized from hexane yielding g. of4- methoxy-l-isovaleronaphthone, M.P. 59.5-61.5 C.

Analysis for: C H O .Calculated: C, 79.31; H, 7.49. Found: C, 79.02; H,7.34.

STEP B.4-HYDR OXY-l-IS OVALERONAPHTHONE A mixture of 10 g. of4-methoxy-l-isovaleronaphthone and 20 g. of pyridine hydrochloride isheated at 205 C.

for 1 hour. After cooling to 80 C. the mixture is suspended in 200 ml.of 10% hydrochloric acid. A dark oil separates and is extracted withether and the ethereal solution extracted with 10% aqueous sodiumhydroxide. Acidification of the alkaline extract with hydrochloric acidresults in the precipitation of a solid which, after recrystallizationfrom a 1:1 mixture of benzene and hexane, yields 2 g. of 4-hydroxy 1isovaleronaphthone, M.P. 133- 135 C.

Analysis for: C H O .Calculated: C, 78.92; H, 7.06. Found: C, 78.93; H,7.00.

STEP C.ETHYL (4-ISOVALERYL-1-N APHTHYLOXY) ACETATE4-hydroxy-l-isovaleronaphthone (9.1 g., 0.04 mole) is added to asolution of 130 ml. of absolute ethanol containing 0.048 mole of sodiumethoxide. After stirring for 10 min, 8 g. (0.048 mole) of ethylbromoacetate is added. After refluxing for 17 hours, the reactionmixture is filtered to remove salt, and the ethanol is then removedunder reduced pressure. The residue is crystallized from hexane andyields 8.5 g. of ethyl (4-isovaleryl-1-naphthyloxy)acetate, M.P. 5759 C.

Analysis for: C H O .--Calculated: C, 72.59; H, 7.05. Found: C, 72.29;H, 7.00.

The ethyl (4-isovaleryl-l-naphthyloxy)acetate obtained as describedabove may then be converted to the corresponding acid, if desired, bysuspending the said ethyl ester in 100 ml. of 2 N sodium hydroxidecontaining 30 ml. of ethanol, refluxing the mixture for one hour,cooling and acidifying with hydrochloric acid. The resulting precipitateis then filtered and recrystallized from a mixture of benzene and hexaneto yield (4-isovaleryl-1-naphthyloxy) acetic acid, melting at 120-121.5C.

Alternatively, the (4-isovaleryl 1 naphthyloxy) acetic acid may also beprepared by the procedure described in Example 21.

EXAMPLE 3 (5-metlzyl-7-batyryl-1-naphthyloxy)acetic acid STEPA.8-HETHOXY4-MIETHYL-2-BUTYRO- LNAPHTHONE A solution of 2.0 g. (0.012mole) of 1-methoxy-5- methylnaphthalene in 4.0 g. (0.046 mole) ofbutyric acid is saturated with boron trifluoride at 10 C. The solutionis treated by substantially the same method described in Example 2, StepA, yielding 2.62 g. of a viscous yellow liquid which is a mixture of 80%of 8-methoxy-4-methyl- 2-butyronaphthone and 20% of other isomers.

STEP B.8-HYDROXY-l-WIETHYL-Z-BUTYRO- NAPHTHONE A mixture of 5.0 g.(2.021 mole) of the above mixture of isomers and 15.0 g. (0.13 mole) ofpyridine hydrochloride is treated substantially as described in Example1, Step C, to give 2.32 g. of a brown solid which is crude8-hyd-roxy-4-methyl 2 butyronaphthone (the other isomers remain in theorganic solvent upon treatment with alkali). Recrystallization twicefrom aqueous isopropyl alcohol gives pure 8-hydroxy-4 methyl 2butyronaphthone, M.P. 178-180 C.

Analysis for: C H O .Calculated: C, 78.92; H, 7.06. Found: C, 78.58; H,7.35.

STEP C. 5-METHYL-7-BUTYRYL-1- NAPHTHYLOXY) ACETIC ACID8-hydroxy-4-methyl-Z-butyronaphthone (1.0 g., 0.0044 mole) is added to asolution of 35 ml. of absolute ethanol containing 0.0053 mole of sodiumethoxide and then 0.88 g. (0.0053 mole) of ethyl bromoacetate is addedand the solution is treated in essentially the same manner described inExample 1, Step D, to give 1.04 g. of a brown solid. Repeatedcrystallization from a mixture of benzene and cyclohexane gives(5-methy1-7-butyry1-l- 10 naphthyloxy)acetic acid in the form of a whitesolid, M.P. l52.5154 C.

Analysis for: C H O .Calculated: C, 71.31; H, 6.34. Found: C, 71.06; H,6.47.

EXAMPLE 4 (8-butyryl-2-naplzthyloxy)acetic acid STEP A.7-AMINO-l-BUTYRONAPHTHONE HYDROCHLORIDE Z-aCetamidonaphthalene, (18.5 g., 0.1mole), aluminum chloride 167 g. (0.5 mole) and 400 cc. carbon disulfideare mixed and stirred rapidly with a Hershberg stirrer. The mixture iscooled to 0 C. and 13.3 g. (0.125 mole) butyryl chloride added during 20minutes. The mixture changes from colorless to yellow and at the end ofthe addition a gum-oil separates. This mixture is stirred at 0 C. for 3hours, then stirred 1 hour as the mixture slowly comes to roomtemperature. After standing at room temperature overnight, hydrogenchloride is expelled by stirring and heating on a steam bath for 1 hour.After cooling to room temperature, the upper carbon disulfide layer isremoved and 300 g. of ice added slowly to the stirred residue. Afterstirring /2 hour, ml. concentrated hydrochloric acid is added and thismixture then is stirred and heated on a steam bath 1 /2 hours. Oncooling, an oil solidifies and is collected by filtration. The thusobtained yellow 7-amino-l-butyronaphthone hydrochloride is trituratedtwice with isopropyl ether to yield 24 g. (94%), of product, M.P. 163170C. One recrystallization from alcohol raises the M.P. to 177 181 C.

Analysis for: C H NO'HCl.- Calculated: C, 67.32; H, 6.46; N, 5.61.Found: C, 67.17; H, 6.55; N, 5.55.

STEP B.7-HYDROXY-1-BUTYRON A'PHTHON E 7-arnino 1 butyronaphthonehydrochloride (10.0 g., 0.04 mole) is dissolved in a mixture of 10 ml.of glacial acetic acid, 10 ml. of concentrated sulfuric acid and 30 ml.of water. This solution is cooled to 0 C. and 3.3 g. (0.048 mole) ofsodium nitrite in 10 ml. of Water is added slowly keeping thetemperature below 5 C. This diazo solution is left at 0 C. for 15minutes and then added dropwise over 7 minutes to a stirred, refluxingmixture of 40 ml. of concentrated sulfuric acid and ml. of water in anitrogen atmosphere. The mixture is stirred and refluxed three minutesand then immediately poured over 400 g. of crushed ice. After 1 hour,the dark gum is repeatedly extracted with portions of boiling hexanewhich, on cooling, precipitates 3.25 g. (38%) of 7-hydroxy-l-butyronaphthone as yellow rosettes, M.P. 79- 83 C. Anadditional recrystallization (with charcoal) from hexane raises the M.P.to 84-85 C.

Analysis for: C H O .Calculated: C, 78.48; H, 6.59. Found: C, 78.49; H,6.67.

STEP C.(S-BUTYRYL-Z-YAPHTHYLOXY)ACETIC ACID 7-hydroxy-l-butyronaphthone(2.14 g., 0.01 mole) is dissolved in 35 ml. of absolute ethanolcontaining 0.012 mole sodium ethoxide. After this solution has refluxedfor 10 minutes, 3.3 g. ethyl bromoacetate (0.02 mole) is added and thesolution then is treated by substantially the same method described inExample 1, Step D, to give a precipitated oil which is scratched andsolidified to yield 2.6 g. (97%) of (8-butyryl-2-naphthyloxy)acetic acidas a light yellow solid, M.P. 109-115 C. Recrystallization from a 2:1mixture of benzene and cyclohexane increases the M.P. to 1l8-120 C.

Analysis for: C H O .Calculated: C, 70.57; H, 5.92. Found: C, 70.82; H,6.11.

1 1 EmMPLE 5 STEP A.4 CHLORO-l-HYDROXY-2 BUTYRO- NAPHTHONE To a solutionof 10.7 g. (0.05 mole) of 1-hydroxy-2- butyronaphthone in 200 ml. ofglacial acetic acid is added dropwise 5.4 g. (0.05 mole) oftert.-butylhypochlorite. The reaction mixture is held at 100 C. forforty-five minutes and then poured into 300 ml. of water. An oilseparates, which solidifies and is removed by filtration.Recrystallization from hexane yields 6.5 g. of 4-chloro-1-hydroxy-2-butyronaphthone, M.P. 59.561 C.

Analysis for: C H ClO .Calculated: C, 67.61; H, 5.27. Found: C, 67.33;H, 5.36.

STEP B.(4-CHLOEO-2-BUTYRYIr'1-NAPHTHYLOXY) ACETI'C ACID A mixture of 8g. (0.032 mole) of 4-chloro-1-hydroxy- Z-butyronap-hthone, 10.5 g.(0.076 mole) of potassium carbonate, 6.3 g. (0.038 mole) of ethylbromoacetate and 100 ml. of N,N-dimethylformamide is stirred at roomtemperature for 17 hours. Water is added until all the inorganic saltshave dissolved and the solution then is extracted with ether. The etherlayer is separated and the solvent removed. The resulting dark oil issuspended in 100 ml. of 2 N aqueous potassium hYdIOXldC. The mixture isboiled for forty-five minutes, acidified with hydrochloric acid andextracted with ether. The ether solution is extracted with aqueoussodium bicarbonate, and the bicarbonate extract then is acidifiedwhereupon a solid separates. Recrystallization from a mixture of benzeneand hexane yields 4 g. of (4-chloro-2-butyryl-l-naphthyloxy) aceticacid, M.P. 7476 C.

Analysis for: C H ClO .-Calculated: C, 62.65; H, 4.93. Found: C, 62.38;H, 5.10.

EXAMPLE 6 (Z-ch lro-4-butyiyl-1 -naphthyloxy) acetic acid STEP A.3CHL ORO-et HYDROXY-LBUTYRO- :NAPHTHONE Aluminum chloride, 26.6 g., is added toa mixture of 17.8 g. (0.1 mole) of 2-chloro-1-naphthol, 10.6 g. (0.1mole) of butyryl chloride and 200 ml. of nitrobenzene. The resultingblack solution is allowed to stir for 20 hours at room temperature andthe reaction mixture then is poured onto a mixture of 100 g. of ice, 100g. of Water and 100 g. of concentrated hydrochloric acid. The organiclayer is diluted with 200 ml. of ether, separated from the aqueouslayer, and then extracted with 20% aqueous sodium hydroxide.Acidification of the alkaline extract yields a dark solid which, afterrecrystallization from a mixture of benzene and hexane gives 5.5 g. of3-chloro-4-hydroxy-l-butyronaphthone, M.P. 111-113" C. Analysis for: C HClO .-Calculated: C, 67.61; H, 5.27. Found: C, 67.79; H, 5.38.

STEP B.-(2-CHDORO-4-BUTYRYL1-NAPHTHYLOXY) ACETIC ACID To a solution ofg. (0.02 mole) of 3-chloro-4-hydroxy-l-butyronaphthone in 100 ml. ofabsolute ethanol there is added 0.22 mole of sodium hydride. Afterstirring for ten minutes, 3.33 g. (0.022 mole) of ethyl bromoacetate isadded to the clear solution and the reaction mixture is treated insubstantially the same manner described in Example 1, Step D, whereuponthe product precipitates. After recrystallization from benzene, 3 g. of(2-chloro-4-butyryl-l-naphthyloxy)acetic acid is obtained, M.P. 124125C.

Analysis for: C H C1O .-Calcu1ated: C, 62.65; H, 4.93. Found: C, 62.77;H, 5.02.

12 EXAMPLE 7 (5 -bulyry I-Z-naphthyloxy acetic acid STEPA.6-hIETHOXY1-BUTYRONA PHTHONE In a 2 liter three-necked flask fittedwith a stirrer, reflux condenser, drying tube, dropping funnel andheating mantle, there is placed 19.5 g. (0.8 mole) of magnesiumturnings. Fifty ml. of ether, a crystal of iodine and 1 ml. of ethylenedibromide then are added. As soon as the vigorous reaction begins, asolution of 114 g. (0.4 mole) of 6-methoxy-1-iodonaphthalene in 570 ml.of anhydrous ether is added over a 40 minute period. The mixture then isheated under reflux with stirring for one hour and then a solution of55.2 g. (0.8 mole) of butyronitrile in 300 ml. of ether is added over a45 minute period and refluxing and stirring continued for 3 hours. Thereaction then is cooled to 10 C. and 500 ml. of ammonium chloridesolution added. After vigorous agitation, the ether layer is separatedand extracted with a 600 ml. and two 200 ml. portions of 1 N sulfuricacid. The acid extracts are combined and heated at C. for one hourwhereupon an oily product separates and is extracted into ether. Theether solution is washed with water, dried with sodium sulfate and thenconcentrated in vacuo to give 54 g. of 6-rnethoxy-1-butyr0naphthone as alight yellow oil, n 1.6010, which is purified by evaporativedistillation at 145 C. and 0.05 mm.

pressure.

Analysis for: C H O .Calculated: C, 78.92; H, 7.05. Found: C, 79.06; H,7.07.

STEP B.6-HYDR OXY-l-BUTYRONAPHTHONE Eight grams of6-methoxybutyronaphthone and 24 grams of pyridine hydrochloride aretreated by substantially the same method described in Step C of Example1 to give 7.0 g. of 6-hydr0xy-1-butyronaphthone. Recrystallization ofthe product from n-butyl chloride gives material melting at 83-84 C.

Analysis for: C I-I O .Calculated: C, 78.48; H, 6.59. Found: C, 78.14;H, 6.73.

STEP C.(5BUTYRYL-2 NAPHTHYLOXY)ACE'IIC ACID 6-l1ydroxy-l-butyronaphthone(19.3 g., 0.09 mole) is added to a solution of 0.095 mole of sodiumethoxide in 300 ml. of ethyl alcohol. A clear solution results to whichis added 18.03 g. (0.108 mole) of ethyl bromoacetate. The solution istreated by substantially the same method described in Example 1, Step D.The product obtained is recrystallized from benzene to provide 17.2 g.(IJfiSSSbutyIyI-Z -naphthyloxy)acetic acid, M.P. 113

Analysis for: C H O .Calculated: C, 70.57; H, 5.92. Found: C, 70.62; H,6.06.

EXAMPLE 8 (2-methyl-4-butyryl-1-naphihyloxy acetic acid STEP A.(Z-HETHYL-l-NAPHTHYLOXY) ACETIC ACID (Z-methyl-l-naphthyloxy) aceticacid (6.5 g., 0.03 mole) is dissolved in 60 ml. of carbon disulfide.This solution is stirred and 12.0 g. (0.09 mole) aluminum chloride isadded and then 3.5 g. (0.033 mole) of n-butyryl chloride is added. Themixture is stirred at room temperature for 1 hour, then stirred underreflux 3 hours. After cooling to room temperature, 50 ml. of a mixtureof ice and Water is added and then acidified with 2% N hydrochloricacid. The oily product is extracted into ether. The ethereal solution isdried over sodium sulfate and filtered through Pilter-Cel and charcoal,then concentrated, yielding 8.7 g. of a red oil. The oil is dissolved in30 ml. of a 1:1 mixture of benzene-cyclohexane and cooled to yield 5.1g. of a light pink solid, M.P. 114-117" C. Recrystallization frombenzene gives (2methyl-4-butyryl-1-naphthyloxy)acetic acid, M.P. 116-119C.

Analysis for: C H O .Calculated: C, 71.31; H, 6.34. Found: C, 71.34; H,6.25.

EXAMPLE 9 (6-pr0pi0nyl-Z-naplzlhyloxy acetic acid Three grams (0.015mole) of 6-hydroxy-2-propionaphthone is dissolved in 100 ml. of warmisopropyl alcohol and to this clear solution is added 0.019 mole sodiumhydride and then 0.019 mole ethyl bromoacetate. This solution then istreated by substantially the same method described in Example 1, Step D,to give (6-propionyl-2- naphthyloxy)acetic acid which is collected byfiltration, Washed with Water and dried. After recrystallization fromalcohol, the product melts at 175-177 C.

Analysis for: C H O .-Calculated: C, 69.75; H, 5.46. Found: C, 69.45; H,5.62.

EXAMPLE 10 (4-propi0nyl-1-naplztizyl0xy acetic acid To 300 ml. ofisopropyl alcohol there is added 0.11 mole of sodium hydride and then20.0 g. (0.1 mole) of 4-hydroxy-l-propionaphthone. A homogeneoussolution results to which is added 18.37 g. (0.11 mole) of ethylbromoacetate and the reaction is carried out in substantially the samemanner as described in Example 1, Step D, to yield 7.6 g. of(4-propiony1-l-naphthyloxy)acetic acid, M.P. 189-191 C.Recrystallization from isopropyl alcohol raises the M.P. to 190-193" C.

Analysis for: C H O .Calculated: C, 69.75; H, 5.46. Found: C, 69.32; H,5.69.

EXAMPLE 1 1 (4-bntyryl-J-naplzzhyloxy)acetic acid To a solution of 27.2g. (0.134 mole) (l-naphthyloxy) acetic acid in 200 ml. carbon disulfideis added 15.8 g. (0.148 mole) n-butyryl chloride. The solution is cooledto 0 C. and 50.8 g. (0.38 mole) aluminum chloride (anhydrous) is addedover 15 minutes and the reaction then carried out in substantially thesame manner described in Example 8, Step B. A solid precipitate isobtained, filtered and washed Well with water. The solid,(4-butyryl-I-naphthyloxy)acetic acid is dissolved in 300 ml. of benzeneand filtered through diatomaceous earth and charcoal and cooled andcollected to yield 37 g. of a yellow solid, M.P. 125-132 C. Afterrecrystallization from 75% alcohol, the (4-butyryl-l-naphthyloxy)aceticacid melts at 137-139 C.

Analysis for: C H O .Calculated: C, 70.57; H, 5.92. Found: C, 70.41; H,6.03.

EXAMPLE 12 [4-(a-ethylbutyiyl) -1-naphtl1yl0xy]acetic acid To a Wellstirred, cooled mixture of 25.2 g. (0.125 mole) of (1-naphthyloxy)aceticacid and 16.7 g. (0.14 mole) of a-ethylbutyryl chloride in 500 ml. ofcarbon disulfide, there is added 53.2 g. (0.4 mole) of aluminumchloride. The mixture is treated by substantially the same methoddescribed in Example 8, Step B, to give a solid which separates and uponrecrystallization from a mixture of benzene and hexane yields 12 g. of[4-(a-ethylbutyryl)- l-naphthyloxy1acetic acid, melting point111.5-112.5 C.

Analysis for: C H O .-Calculated: C, 71.98; H, 6.71. Found: C, 71.90; H,6.75.

14 EXAMPLE 13 (4-butyryl-Z-naphthyloxy acetic acid STEPA.3-\IETHOXY-1-BUTYRONAPHTHONE A Grig-nard reagent is prepared from 1.85g. (0.076 mole) magnesium turnings and 9.4 g. (0.076 mole) n-propylbromide in ml. absolute ether. After the reagent has refluxed andstirred for 1 hour, 3-methoxyl-cyanonaphthalene (11.6 g., 0.0635 mole)dissolved in 500 ml. of ether is added slowly. The reaction of thesematerials is carried out substantially as described in Example 1, StepB, to yield 8.3 g. of 3-methoxy-1-butyronaphthone as a brown oil, 111.5980. Evaporative distillation produces a slightly yellow oil samplewith an evaporative boiling point of 140 C. at 0.1 mm. pressure, n1.5986.

Analysis for: C H O .-Calculated: C, 78.92; H, 7.06. Found: C, 78.94; H,6.98.

STEP B.-3-HYDROXY-l-BUTYRONAPHTHONE Pyridine (40 ml., 0.5 mole) andconcentrated hydrochloric acid (44 ml., 0.5 mole) are cautiously mixedin a round-bottomed flask and heated to 210 C. in a metal bath. To thismolten anhydrous pyridine hydrochloride is added 11.8 g. (0.052 mole) of3-methoxy-1-butyronaphthone and the solution is then treated bysubstantially the same method as described in Example 1, Step C, toyield 8.9 g. of 3-hydroxy-l-butyronaphthone, M.P. 118 C.Recrystallization from n-butyl chloride yields White flakes, M.P.120-122 C.

Analysis for: C H O .-Calculated: C, 78.48; H, 6.59. Found: C, 78.49; H,6.63.

STEP C.(-BUTYRYL-ZQNAPHTHYLOXY) ACETIC AC1).

3-hydroxy-l-butyronaphthone (8.35 g., 0.039 mole) is dissolved in 100ml. of absolute ethyl alcohol containing 0.043 mole sodium ethoxide. Themixture is heated and stirred for 5 minutes. Then 7.4 g. (0.044 mole) ofethyl brornoacetate is added and the reaction then is carried out bysubstantially the same method described in Example 1, Step D, to yield9.5 g. of (4-butyryl-2-naphthyloxy)acetic acid, M.P. 111-116 C.Recrystallization from benzene, then isopropyl alcohol yields ananalytical sample with a melting point of 122-124 C.

Analysis for: C H O Calculated: C, 70.57; H,

i 5.92. Found: C, 70.26; H, 5.97.

EXAMPLE 14 6 -b zttyiyl-l -naphthyl0xy acetic acid STEP A.--5-METHOXY2-BUTYRONAPHTHONE A Grignard reagent is prepared from 18.5 g. (0.15mole) n-propyl bromide, 3.6 g. (0.15 mole) magnesium turniugs and atrace of iodine in 175 ml. ether. This reagent is stirred and refluxedfor one hour. Then 22.0 g. (0.12 mole) 5-methoxy-2-cyanonaphthalene in400 ml. ether is added over one hour. The reaction mixture then istreated by substantially the same method described in Example 1, Step13, to give 5-methoxy-2-butyronaphthone in the form of yellow crystalsweighing 19 g., M.P. 56-61 C. A recrystallization from isopropyl alcoholraises the M.P. to 60-63 C.

Analysis for: C H O .-Calculated: C, 78.92; H, 7.06. Found: C, 79.15; H,7.11.

STEP B.5-HYDROXY-2-BUTYRONAPHTHONE The dehydration of aqueous pyridinehydrochloride to anhydrous pyridine hydrochloride for this demethylationis accomplished by heating 64 ml. (0.8 mole) pyridine and 70 ml. (0.8mole) concentrated hydrochloric acid to 210 C. over approximately /2hour. To this hot melt is added 19.0 g. (0.084 mole)S-methoxy-Z-butyronaphthone and the resulting dark homogeneous solutionthen is treated by substantially the same method described in Example 1,Step C, to give 14 g. of 5-hydroxy-2-butyronaphthone weighing 14 g.,M.P. -137" C. Recrystal- 15 lization from n-butyl chloride raises theM.P. to 138- 140 C.

Analysis for: C H O .Calculated: C, 78.48; H. 6.59. Found: C, 78.18; H,6.82. STEP C.-(G-BUT'YRYL-l-NAPHTHYLOXY)ACETIC ACID5-hydroxy-2-butyronaphthone (13.8 g., 0.065 mole) is dissolved in 200ml. absolute ethyl alcohol containing 0.078 mole sodium ethoxide. Thismixture is refluxed 10 minutes, then 21.7 g. (0.13 mole) ethylbromoacetate is added and the mixture treated by substantially the samemethod described in Example 1, Step D, to give a solid which, afterrecrystallization from 50 ml. of a 50% mixture of ethanol and water,yields 5.8 g. of (6-butyryl-1- naphthyloxy)acetic acid, M.P. 130133 C.One recrystallization from benzene raises the melting point to 134- 136C.

Analysis for: C H O .Calculated: C, 70.57; H, 5.92. Found: C, 70.46; H,5.78.

EXAMPLE 15 (5 -ch Zora-4 -baryry l-J maph thy loxy acetic acid STEP A.-(5-CHLORO-1 NAPHTHYLOXY ACETIC ACID To a solution of 16. g. (0.09 mole)of 5-chloro-1- naphthol in 200 ml. of absolute ethanol containing 0.11mole of sodium ethoxide, there is added, after stirring for fiveminutes, 18.3 g. (0.11 mole) of ethyl bromoacetate, and the reactionmixture then is treated by substantially the same method described inExample 1, Step D, to give (5-chloro-1-naphthyloxy)acetic acid which,after recrystallization from a mixture of benzene and methanol, melts at170181 C., yield 14.7 g.

Analysis for: C H ClO .Calculated: C, 60.90; H, 3.83. Found: C, 61.16;H, 4.02.

STEP B.-(5-CHLORO-4BUTYRYL-1-NAPHTHYLOXY) ACETIC ACID Aluminum chloride(24.6 g., 0.18 mole) is added slowly to a well stirred mixture of 12.3g. (0.05 mole) of (5- chloro-l-naphthyloxy)acetic acid, 6.3 g. (0.06mole) of n-butyryl chloride and 300 ml. of carbon disulfide. Thereaction mixture is treated by substantially the same method asdescribed in Example 8, Step B, to give a solid which, afterrecrystallization from a mixture of benzene and methanol, yields 12.4 g.of (5-chloro-4-butyryl-1- naphthyloxy)acetic acid, M.P. 164-165.5 C.

Analysis for: C H ClO .-Calculated: C, 62.65; H, 4.93. Found: C, 62.75;H, 4.93.

EXAMPLE 16 (3 -m ethy l-7-butyry l-1 -naph!hylxy acetic acid STEPA.1METHOXY-3-METHYLNAPHTHALENE A solution of 5.0 g. (0.0316 mole) of3-methyl-1- naphthol in 14 ml. of 2.5 N sodium hydroxide and 15 ml. ofwater is warmed to 40 C. under nitrogen and 3.98 g. (0.0316 mole) ofdimethyl sulfate is added over a 10 minute period with stirring. Thereaction mixture then is treated by substantially the same methoddescribed in Example 1, Step A. The oily product obtained is extractedwith ether, washed with water, dried and concentrated under reducedpressure, giving 1-methoxy 3-methylnaphthylene which distills at 9597 C.at 0.5 mm., yield 5.1' g.

Analysis for: C H O.Calculated: C, 83.69; H, 7.02. Found: C, 83.67; H,7.07.

STEP B.8METHOXY-6METHYL-2-BUTYRO- NAPHTHONE A mixture of 4.0 g. (0.023mole) of 1-methoxy-3-methylnaphthalene, 3.09 g. (0.029 mole) of butyrylchloride, and 50 ml. of nitrobenzene is cooled to C. and 3.71 g. (0.028mole) of aluminum chloride is added over 1%. hours. The mixture then istreated by substantially the same method described in Example 8, Step B,yielding 4.3 g. of a viscous yellow oil. Upon evaporative distillation,the distillate solidifies to a yellow solid which, afterrecrystallization from methylcyclohexane, gives8-methoxy-6-methyl-2-butyronaphthone in the form of a pale yellow solid,M.P. 93.595.5 C.

Analysis for: C H O .-Calculated: C, 79.31; H, 7.49. Found: c, 79.30; H,7.22.

STEP C.S-HYDROXY-6-METHYL-2-BUTYRO- 'NAPHTHONE To a solution of 2.0 g.(0.009 mole) of the product of Step C in 50 ml. of absolute ethanolcontaining 0.0091 mole of sodium ethoxide, there is added, after 5minutes, 1.8 g. (0.011 mole) of ethyl brornoacetate and the mixture thenis refluxed for 4 hours and treated in substantially the same mannerdescribed in Example 1, Step D, togive 1.53 g. of(3-methyl-7-butyryl-l-naphthyloxy)acetic acid in the form of a tansolid. Recrystallization from a 50:50 mixture of benzene and cyclohexanegives the product in the form of a white solid, M.P. 141.5143 C.

Analysis for: C H O .Calcu1ated: C, 71.31; H, 6.34. Found: C, 71.23; H,6.63.

EXAMPLE 17 (4-'bzztyryl-3-rnethyl-1 naphthyloxy)acetic acid STEPA.-4-BHOMO-3-\IETHYL-1-METHOXY- 'NAPHTHALENE A solution of 34.4 g. (0.20mole) of 1-methoxy-3- methylnaphthalene, prepared as described inExample 16, Step A, in 400 ml. of glacial acetic acid is heated to C.Then a solution of 33.6 g. (0.21 mole) of bromine in ml. of glacialacetic acid is added dropwise with stirring while maintaining thetemperature at 80 C. The addition requires about 2 hours. Stirring iscontinued for 15 minacetic acid gives pure4-brorno3-rnethyl-l-methoxynaphthalene melting at 6263.5 C.

Analysis for: C H BrO.Calculated: C, 57.39; H, 4.42. Found: C, 57.22; H,4.44.

STEP B.4 l-HYDROXYBUTYL) -3-METHYL-1- METHOXY-NAPHTHALENE A Grignardreagent is prepared from 1.34 g. (0.055 mole) of magnesium and 12.56 g.(0.05 mole) of 4-bromo- 3-methyl-l-methoxynaphthalene in 60. ml. oftetrahydrofuran; the reaction being initiated with several drops ofethylene dibromide. The Grignard reagent is cooled to -30 C. and asolution of 3.97 g. (0.055 mole) of butyraldehy' de in 40 ml. oftetrahydrofuran is added dropwise with stirring over a 25 minute period.Then the mixture is placed in an ice bath and stirred for 20 hours asthe temperature rises slowly to 25 C. The tetrahydrofuran then isremoved under reduced pressure and 100 ml. of ether is added, themixture cooled in ice md decomposed by adding a solution of 5.35 g. (0.1mole) of ammonium chloride in 50 ml. of water. The ether layer isseparated, washed with water, dried, and concentrated under reducedpressure, yielding 11.8 g. of4-(l-hydroxybutyl)-3-methyli-methoxynaphthalene as a viscous yellow oil.

17 STEP C.4-BUTYRYL-3-METHYL-l-METHOXY- NAPHTHALENE A pyridine-chromiumcomplex is prepared by cooling 500 ml. of pyridine to 15 C. and adding50.0 g. (0.5 mole) of chromium trioxide in small portions with stirring.The addition requires about /2 hour and stirring is continued foranother /2 hour as the temperature rises to 25 C. The suspension iscooled to C. and a solution of 43.0 g. of4-(l-hydroxybutyl)-3-methyl-l-methoxynaphthalene in 500 ml. of pyridineis added. The mixture is stirred at 5 C. for 1% hours and at roomtemperature overnight. The dark mixture which results is poured into 5liters of water and then extracted with ether. The ether extract iswashed with water, 1 N hydrochloric acid, 1 N sodium hydroxide, andagain with water, and dried and concentrated under reduced pressure. Ayellow liquid is obtained (36.2 g.). Pure4-butyryl-3-methyl-1-methoxynaphthalene distills at 145l50 C. at 0.5 mm.pressure, 11 1.5875.

Analysis for: C H O .Calcu1ated: C, 79.31; H, 7.49. Found: C, 78.94; H,7.34.

STEP D.4-BUTYRYL-3-METHYL-1-\IAPHTHOL A mixture of 3.22 g. (0.14 mole)of sodium and 25 ml. of pyridine is heated under nitrogen at 160-180 C.for 15 minutes with rapid stirring. Then 4.85 g. (0.02 mole) of4-butyryl-3-methyl-l-methoxynaphthalene in 20 ml. of pyridine is addedand excess pyridine is allowed to distill out a side arm tube as thebath temperature is raised to 200 C. The mixture is heated at 200 C. for5 hours. After cooling, several milliliters of pyridine are addedfollowed by the cautious addition of 50 ml. of Water. The aqueoussolution is washed with ether, the ether solution washed with 1 Nhydrochloric acid and then extracted with 1 N sodium hydroxide. Thebasic extract and aqueous solution are combined and acidified withexcess hydrochloric acid. The solid which separates is extracted intoether, the ether extract washed with Water, dried, and concentratedunder reduced pressure. A yellow solid is obtained in 71% yield, M.P.144147.5 C. Recrystallization from ethanol-water gives pure4-butyryl-3-methyl-1- naphthol as a pale yellow solid, M.P. 148.5-149.5C.

Analysis for: C H O .-Calculated: C, 78.92; H, 7.06. Found: C, 78.78; H,7.35.

STEP E.(4-BUTYRYL-3-METHYL-l-NAPHTHYLOXY) ACETIC ACID4-butyryl-3-methyl-l-naphthol (0.78 g., 0.0034 mole) is added to asolution of 25 ml. of absolute ethanol containing 0.0034 mole of sodiumethoxide and then 0.68 g. (0.004 mole) of ethyl bromoacetate is added.The solution is treated in essentially the same manner described inExample 1, Step D, to give an 84% yield of(4-butyryl-3-methyl-l-naphthyloxy)acetic acid as an oil which solidifiesto a pale yellow solid, M.P. 126129 C. Recrystallization from n-butylchloride gives a white solid, M.P. 131132.5 C.

Analysis for: C H O .-Calculated: C, 71.31; H, 6.34. Found: C, 71.15; H,6.56.

EXAMPLE 18 (4-bzttyryl-5-methyl-1 -naphthyloxy)acetic acid STEPA.l-HYDROXY-l-METHYL-LZ,3,4-TETRAHYDRO- S-NAPHTHOL A Grignard reagent isprepared by treating 43.8 g. (1.8 mole) of magnesium with 256 g. (1.8mole) of methyl iodide in 900 ml. of ether under nitrogen. Then 74.0 g.(0.36 mole) of 5-acetoxy-3,4-dihydro-1(2H)-naphthalenone in 750 ml. oftetrahydrofuran is added and the mixture stirred under nitrogen for 48hours. The ether and tetrahydrofuran then are removed under reducedpressure and 500 ml. of ether added and the mixture decomposed by addingexcess aqueous ammonium chloride. The ether layer is separated, washedwith a mixture of water and dilute hydrochloric acid, dried, and concen-18 trated under reduced pressure to give 63 g. of l-hydroxy-1-methyl-1,2,3,4-tetr-ahydro-5-naphthol as a yellow solid. STEP B.ETHY-L(5-HYDRoXY-5METHYL-55,7,8- TEIRAHYDRO-l-NAPHTHYLOXY)ACETATE The 63 g.(0.35 mole) of crude l-hydroxy-l-methyl- 1,2,3,4-tetrahydro-5-naphtholis treated with 65.1 g. (0.39 mole) of ethyl bromoacetate and 16.7 g.(0.37 mole) of sodium ethoxide as in Example 2, Step C, to give crudeethyl (5-hydroxy-5-methyl-5,6,7,8-tetrahydro- 1-naphthyl0xy)acetate innearly quantitative yield as a dark yellow oil.

STEP C.ETHYL (7,8 DIHYDRO-5-WIETHYL1- NAPHTHYLOXY)ACETATE The crudeethyl (S-hydroxy 5 methyl-5,6,7,8-tetrahydro-l-naphthyloxy)acetate isdehydrated by dissolving 32.4 g. (0.123 mole) thereof in 40 ml. ofbenzene and 75 ml. of pyridine and adding 20 g. (0.13 mole) ofphosphorous oxychloride. The mixture is stirred on the steam bath for 2hours and then the solvents are removed under reduced pressure. Theresidual mixture of oil and solid materials is taken up in 250 ml. ofether and ml. of water, the ether layer separated, washed with dilutehydrochloric acid and water, dried, and concentrated under reducedpressure to give 26.1 g. (87%) of ethyl(7,8-dihydro-S-methyl-l-naphthyloxy) acetate as a dark yellow oil.

STEP D.ETHYL (5-\IETHYL-5,6,7,8-TETRAHYDRO-1- NAPHTHYLOXY) ACETATE Thecrude ethyl (7,8-dihydro-5-methyl-1-naphthyloxy) acetate is hydrogenatedby dissolving 53.0 g. (0.215 mole) in 200 ml. of absolute ethanol andshaking with 5% palladium on carbon under 30 lbs/sq. in. of hydrogenuntil approximately the theoretical quantity of 'hydrogen is taken upand hydrogenation ceases. The mixture is filtered under nitrogen and thefiltrate concentrated under reduced pressure to give a nearlyquantitative yield of ethyl (5- rnethyl-5 ,6,7,8-tetrahydro 1-naphthyloxy) acetate.

STEP E.-(B-METHYL E,6,7,STETRAHYDRO-1- NAPHTHYLOXY) A'CETIC A'CID An11.8 g. (0.0476 mole) portion of ethyl (S-methyl-5,6,7,8-tetr-ahydro-l-naphthyloxy)acetate is dissolved in 100 ml. ofethanol, and 5.61 g. (0.10 mole) of potassium hydroxide in 25 ml. ofwater is added. The solution is heated at reflux for /2 hour, theethanol removed under reduced pressure and the salt dissolved in ml. ofwater. The aqueous solution then is Washed with ether and acidified withexcess hydrochloric acid and filtered to give 8.1 g. of a pale tansolid, M.P. 152-155 C. Recrystallization from ethanol-water gives white(S-methyl- 5,6,7,8-tetrahydro-1-naphthy1oxy)acetic acid, M.P. 156.5-158.5 C.

Analysis for: C H O .Calculated: C, 70.89; H, 7.32. Found: C, 70.81; H,7.17.

STEP F.(4-BUTYRYL5-METHYL-5,6,7,8-TETRAHYDRO- 1 NAPHTHYLOXY)ACETIC ACIDBy replacing the (Z-methyl-1-naphthyloxy)acetic acid and the carbondisulfide of Example 8, Step B, with equimolar quantities of(5-methyl-5,6,7,8-tetrahydro-l-naphthyloxy)acetic acid and methylenechloride and extending V the time at reflux to 16 hours, there isobtained a 94% yield of(4-butyryl-5-methyl-5,6,7,S-tetrahydro-l-naphthyloxy)acetic acid as ayellow oil.

STEP G.-ETHYL (AND METHYL) (4-BUTYRYL-5-METH-YL-5,6,7,S-TETRAHYDRO-I-NAPHTHYLOXY)ACETATE water and cold sodiumcarbonate solution, dried, filtered,

and concentrated to give 4.4 g. of ethyl (4-butyryl-5- Methyl(4-butyryl-5-methyl-5,6,7,8-tetrahydro-l-naphthyloxy)acetate, 9.11 g.(0.03 mole), is dissolved in 100 ml. of anhydrous benzene. Then 8.52 g.(0.0375 mole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added andthe mixture is stirred at reflux for 3 hours under nitrogen. Another8.52 g. (0.0375 mole) of the quinone is added and reflux continued foran additional 16 hours. The cooled reaction mixture is filtered and thefiltrate concentrated under reduced pressure to a dark oil. The oil istaken up in 100 ml. of ether, the ether solution washed thoroughly withwater, sodium bicarbonate (cold) and again with water, dried, andconcentrated under reduced pressure to give 5.90 g. of methyl(4-butyryl-5-methyl-1- naphthyloxy)acetate as a pale tan solid.Continued recrystallization from isopropanol-water raised the meltingpoint to 89-94 C.

STEP I.-(4-BUTYRYLfi-NIETHYL-l-NAPHTHYLOXY) ACETIC ACID cedure describedtherein, there is obtained (6-methyl-1- naphthyloxy) acetic acid.

STEP B.(G-METHYL-d-BUTYRYL-l-NAPHTHYLOXY) ACETIC ACID By replacing the(Z-methyld-naphthyloxy)acetic acid of Example 8, Step B by anequimolecular quantity of (6-methyl-l-naphthyloxy)acetic acid andfollowing substantially the same procedure described therein, there isobtained (6-methyl-4-butyryl-l-naphthyloxy)acetic acid.

EXAMPLE 20 V (4-n-valeryl-l-ntzphthyl0xy)acetic acid .By followingsubstantially the same procedure described in Example 8, Step B, butreplacing the (2-methyl-1-naphthyloxy)acetic acid and the butyrylchloride employed therein by equivalent quantities of(l-naphthyloxy)acetic acid and n-valeryl chloride, respectively, thereis obtained (4-n-valeryl-1-naphthyloxy)acetic acid.

EXAMPLE 2l (4-isovaleryl-1umphtlzyloxy acetic acid By replacing the(Z-methyl-l-naphthyloxy)acetic acid and the butyryl chloride employed inExample 8, Step B, by equivalent quantities of (l-naphthyloxy)aceticacid and isovaleryl chloride, respectively, and following substantiallythe same procedure described in Example 8, Step B, there is obtained(4-isovaleryl-l-naphthyloxy) acetic acid, M.P. 12012l.5 C.

20 Analysis for: C H O .Calculated: C, 71.31; H, 6.34. Found: C, 71.37;H, 6.25.

EXAMPLE 22 4 -capr0y l-1 map/1 thyloxy) acetic acid By replacing the(Z-methyl-l-naphthyloxy)acetic acid and butyryl chloride employed inExample 8, Step B, by equimolecular quantities of (l-naphthyl-oxy)aceticacid and caproyl chloride, respectively, and following substantially thesame procedure described in Example 8, Step B, there is obtained(4-caproyl-1-naphthyloxy)acetic acid.

EXAMPLE 23 (4 -cnantlz yl-I -naplz thyl oxy acetic acid By replacing the(Z-methyl-l-naphthyloxy)acetic acid and the butyryl chloride employed inExample 8, Step B, by equimolecular quantities of (l-naphthyloxy)aceticacid and enanthyl chloride, respectively, and following substantiallythe same procedure described in Example 8, Step B, there is obtained(4-enanthyl-l-naphthyloxy) acetic acid.

EXAMPLE 24 [4- ,B-phenylpropionyl) -1-naphthyloxy acetic acid STEPA.(LACETYIrLNAPHTHYLOXY)ACETIC ACID By replacing the(Z-methyl-l-naphthyloxy)acetic acid and the butyryl chloride employed inExample 8, Step B, by equimolecular quantities of (l-naphthyloxy)aceticacid and acetyl chloride, respectively, and following substan tially thesame'procedure described in Example 8, Step B, there is obtained(4-acetyl-l-naphthyloxy)acetic acid.

STEP B.[4-(fi-PHENYLPR-OPIONYL)-1 NAPHTHYL- OXY] ACETIC ACIDEquimolecular quantities of (4-acetyl-1-naphthyloxy) acetic acid andbenzaldehyde are dissolved in a mixture of sodium hydroxide (about 3mole excess) in water and ethanol. The solution is kept at 25-30 C. forabout 16 hours, acidified with hydrochloric acid and the solid thatseparates is collected and dried to give [4-(fi-pheny1-acryloyl)-l-naphthyloxy]acetic acid. The [4-(fl-phenylacryloyl)-l-naphthyloxy]acetic acid is dissolved in isopropyl alcoholand hydrogenated in the presence of 5% palladium on charcoal at 25 C.and at about 750' mm. pressure until the required amount of hydrogen isabsorbed. The solution is then warmed and filtered to remove thecatalyst and the alcohol is removed from the product by evaporation togive [4-(fi-pl1enylpr-opionyl)-1- naphthyloxy]acetic acid.

EXAMPLE 25 (4-cycl0 pcntylcarbony [-1 -naph tlzyloxy acetic acid To aprecooled mixture of l-methoxynaphthalene (0.334 mole),cyclopentanecarbonyl chloride (0.334 mole) and petroleum ether (300 ml.)is added a slight excess of powdered aluminum chloride (0.36 mole) overa period of one hour with stirring. This mixture then is heated at 40 C.for about 6 hours with intermittent stirring, cooled, poured into amixture of ice and water and concentrated hydrochloric acid andextracted with ether. The ether extract then is distilled to givecyclopentyl 4- methoxy-l-naphthyl ketone. Treatment of this product withpyridine hydrochloride by substantially the same procedure described inExample 1, Step C, gives cyclop'entyl 4 hydroxy 1 naphthyl ketone. Thisproduct is added to a solution of sodium ethoxide in ethyl alcohol andthen reacted with a slight excess of ethyl bromo acetate bysubstantially the same procedure described in Example 1, Step D, to give(4-cyclopentylcarbonyl-lnaphthyloxy) acetic acid.

21 EXAMPLE 26 [4- cyclohcxylcarbonyl) -naphthylxy] acetic acid To amixture of equimolecular quantities of l-methoxynaphthalene andcyclohexanecarbonyl chloride in ligroin, a slight excess of aluminumchloride is added gradually with stirring at a temperature of about 15C. After addition is complete, the mixture is allowed to warm to 25 C.and then is stirred for approximately 3 hours and kept at 25-30 C. forapproximately 16 hours. The ligroin is decanted and the residuehydrolyzed with water containing a small amount of concentratedhydrochloric acid to give cyclohexyl 4-methoxy-1-naphthyl ketone. Thisproduct then is treated with pyridine hydrochloride by substantially thesame procedure described in Example 1, Step C, to give cyclohexyl4-hydroxy-1-naphthyl ketone. This product then is added to a solution ofsodium ethoxide in ethyl alcohol and treated with a slight excess ofethyl bromoacetate by substantially the same procedure described inExample 1, Step C, to yield [4-(cyclohexylcarbonyl)-1-naphthyloxy]acetic acid.

EXAMPLE 27 [4- ,B-carboxypropionyl -naphthyl0xy acetic acid4-(B-carboxypropionyl)-1-napl1thol (0.05 mole) is dissolved in 250 ml.of absolute ethanol containing 0.12 mole of sodium ethoxide. After thesolution has refluxed for minutes, 20 g. of ethyl bromoacetate (0.12mole) is added and the solution then is treated by substantially thesame method des ribed in Example 1, Step D, to give a precipitate which,upon recrystallization from a mixture of ethanol and water, yields[4-(B-carboxypropionyl)1-naphthyloxy1acetic acid, M.P. 169-171 C.

EXAMPLE 28 u- (4-batyryl-1-naphthyloxy) propionic acid4-hydroxy-l-butyronaphthone is added to a solution of sodium methoxidein ethyl alcohol and reacted with a slight excess of ethyla-bromopropionate by following the same procedure described in Example1, Step D. The product thus obtained is a-(4-butyryl-l-naphthyloxy)-propionic acid.

EXAMPLE 29 4- (4-bzztyryl-I-naplzthyloxymetlzyl) benzoic acid STEPA.4-CHLOROMETHYLBENZONITRILE p-Tolunitrile (0.854 mole) is placed in a c-necked flask fitted with gas inletoutlet tube, stirrer and thermometer.Stirring is started and the nitrile is heated to 120130 C. Chlorine gasis passed into the liquid at a moderate rate, and the reaction activatedby an incandescent lamp. The addition is continued until the nitriletakes up 30 g. of the gas (about 2 hours). The material is allowed tostand overnight in air whereupon a crystalline mass forms. This iswashed twice with ethanol and dried in air. Concentration of the ethanolsolution to half its volume gives a 57% yield of4-chloromethylbenzonitrile, M.P. 7577 C.

STEP B.4-CHLOROMETHYLBENZOIC ACID 4-chloromethylbenzonitrile (0.164mole) is refluxed and stirred with concentrated hydrochloric acid (500ml.) for about 14 hours. Upon cooling, a solid is obtained which isremoved by filtration and dried in a desiccator to give a 94.5% yield of4-chloromethylbenzoic acid, M.P. 202- 203 C.

STEP C.ETHYL d-GHLOROMETHYLBENZ OATE 4-cl1loromethylbenzoic acid (0.156mole) is dissolved in absolute ethanol (225 ml.) and heated to 60 C. ina 4-necked flask fitted with gas inlet tube, thermometer, stirrer,reflux condenser, and drying tube. Stirring is started and anhydroushydrogen chloride gas is passed in for one hour, the temperature beingmaintained at 5060 C. The solution then is refluxed one hour, cooled andper mitted to stand overnight. The ethanol then is evaporated in vacuo,the residue taken up in ether, washed with 5% sodium carbonate, driedand evaporated to an oil which distills at 9193 C. at 0.6 mm. pressureto give a 74% yield of ethyl 4-chloromethylbenzoate.

STEP D.4- 4-BUTYRYL-1 WAPHTHYLOXYMETHYL) BENZOIC ACID4-hydroxybutyr0naphthone (0.25 mole) is dissolved in anhydrous methanol(500 ml.), and sodium metal (0.2 mole) is added in portions. When allthe sodium dissolves, ethyl 4-chloromethylbenzoate (0.125 mole) is addedand the mixture is refluxed for 19 hours. The volume of methanol isreduced to 200 ml. and the mixture cooled, filtered, water added and themixture extracted with ether. The ether extract is washed with 5% sodiumhydroxide, dried and evaporated to remove the ether. The residue istaken up in 10% sodium hydroxide and heated on a steam bath withstirring for 2 hours. After cooling and acidification With hydrochloricacid, there is obtained 4-(4-butyryl-1- naphthyloxymethyl)benzoic acid.

EXAMPLE 30 3-(4-baty1'yl-1-naphthyl0xymethyl)benzoic acid STEPA.A\;[ETHYL 3 BROMIOMlETHYLBENZOATE 3methylbenzoyl chloride (0.68 mole)is placed in a 4-necked flask, fitted with stirrer, reflux condenser,drying tube, thermometer and dropping funnel, and heated to C. Stirringis started and the temperature maintained at 180 C., and bromine (0.69mole) is added dropwise over a period of about 1 hour. The mixture thenis stirred an additional 1.5 hours at 180 C. and finally cooled. Withstirring maintained, methanol (67 ml.) is added to the mixture dropwiseover an hour. The mixture then is distilled to give the pure productwhich crystallizes upon standing. There is thus obtained a 50% yield ofmethyl 3-bromomethylbenzoate, B.P. 136137 C. at 8 mm. pressure.

STEP B.METHYL 3(4-BUTYRYL-1 NAPHTHYLOXY- METHYL) BENZOATE4-hydroxybutyrophenone (0.09 mole) is dissolved in anhydrous methanol(200 ml.) and sodium metal (0.075 mole) is added in portions. When allthe sodium is dissolved, methyl S-bromomethylbenzoate (0.044 mole) isadded and the mixture refluxed 24 hours. The volume of solvent then isreduced to about 50 m1. and about 250 ml. of water is added. The mixtureis extracted with ether, Washed with 5% sodium hydroxide and water,dried and evaporated to give methyl3-(4-butyryl-1-naphthyloxymethyl)benzoate.

STEP C.3-(4-BUTYRYL1-NAPHTHYLOXYMETHYL) BENZOIC ACID Methyl 3 (4-butyryl41-naphthyloxymet-hyl) benzoate (0.018 mole) is heated on thesteam bath and stirred for 1.5 hours with 10% sodium hydroxide (25 ml.).After cooling and acidification, there is obtained 3-(4 butyryl-1-naphthyloxymethyl)'benzoic acid.

EXAMPLE 31 4- 4 -baIyryl-l -naphthyl0xy benzoz'c acid STEP A.4-(1-NAPHTHYLOXY)BENZOIC ACID Sodium hydride (0.063 mole) is dissolvedin anhydrous ethylene glycol dimethyl ether (50 ml.). To this mixture isadded 0.058 mole of l-naphthol as rapidly as evolution of hydrogen gaspermits. The glycol dimethyl ether is evaporated in vacuo leaving a drysolid. Additional 1- naphthol (0.02 mole) dry copper metal (1 gram) ascatalyst and methyl p-iodo benzoate (0.057 m'ole) are added and thewhole mixed together. This mixture is heated on a Woods metal bath at180200 C. for 5 hours and cooled, yielding a precipitate which is takenup in ethyl acetate. The ethyl acetate solution is extnacted severaltimes with saturated aqueous sodium bicarbonate. The

23 combined aqueous extracts are acidified yielding a precipitate of 4-(l-naphthyloxy)benzoic acid.

STEP B.-4- (-BUTYRYL-bNAPHTHYLOXY) BENZOIC ACID By followingsubstantially the same procedure described in Example 8, Step B, butreplacing the (Z-methylnaphthyloxy) acetic acid employed therein by anequivalent quantity of 4(l-naphthyl-oxyybenzoic acid, there is obtained4-(4- butyryl-l-naphthyloxy)benzoic acid.

EXAMPLE 32 (4-is0capr0yl-1-naphthyloxy acetic acid By replacing the(Z-methyl-l-naphthyloxy)acetic acid and the butyryl chloride employed inExample 8, Step B, by equivalent quantities of (1-naphthyloxy)aceticacid and isocaproyl chloride, respectively, and following substantiallythe same procedure described in Step B of Example 8, there is obtained(4-isocapro-yl-l-naphthyloxy) acetic acid.

EXAMPLE 33 [4- a-ethy lisovaleryl) -naph thylxy1acetic acid By replacingthe (2-ethyl-1-na-phthyloxy)acetic acid and the butyryl chlorideemployed in Example 8, Step B, by equivalent quantities of(1-naphthyloxy) acetic acid and a-ethylisovaleryl chloride and followingsubstantially the same procedure described in Example 8, Step B, thereis obtained [4 (a-ethylisovaleryl)-'1-naphthyloxy] acetic acid.

EXAMPLE 34 (4-cycl0pentaneacetyl-1 -naph thyloxy acetic acid Byreplacing the (Z-methyl-l-naphthyloxy)acetic acid and the butyrylchloride employed in Example 8, Step B, by equimole'cular quantities of(l-naphthyloxy) acetic acid and cyclopentaneacetyl chloride,respectively, and following substantially the same procedure describedin Step B of Example 8, there is obtained(4-cycl'opentaneacetyll-naphthy-loxy) acetic acid.

EXAMPLE 35 (4-cycl0hexaneacetyl-1-naphthyl0xy acetic acid By replacingthe (Z-methyl-I-naphthyloxy)acetic acid and the butyryl chlorideemployed in Example 8, Step B, by equivalent quantities of(l-n'aphthyloxy) acetic acid and cyclohexaneacetyl chloride,respectively, and following substantially the same procedure describedin Example 8, Step B, there is obtained (4-cyclohexaneacetyl-1-naphthyloxy)acetic acid.

EXAMPLE 36 [4- ('y-phenylmercaptobutyiyl) -1-naph thyloxy] acetic acidSTEP A.- [4- ('y-CHLOROBUTYRYL) -I NAPHTHYLOXY] ACEIIC ACID By replacingthe (Z-methyl-l-naphthyloxy)acetic acid and the butyryl chlorideemployed in Example 8, Step B, by equivalent quantities of(1-naphthyloxy)acetic acid and 'y-chlorobutyryl chloride respectively,and following substantially the same procedure described in Step B ofExample 8, there is obtained [4-('y-chlorobutyryl)-lnaphthyloxy] aceticacid.

STEP 'B.-[4- ('y-PHENYLMER'CAPTOBUTYRYL) -1- NAPHTHYLOXY1ACETIC ACID 24give [4 ('y phenyl-rnercaptobutyryl) l-naphthyloxy] acetic acid.

EXAMPLE 37 (4-benzy lmeicaptoacetyl-I -naphthy loxy acetic acid STEPA.(4-CHLOROACETYL-l-NAPHTHYLOXY) ACE'IIC ACID By replacing the(Z-methyld-naphthyloxy)acetic acid and the butyryl chloride employed inExample 8, Step B, by equivalent quantities of (1-na-phthyloxy)aceticacid and chloroacetyl chloride, respectively, and followingsubstantially the same procedure described in Example 8, Step B, the-reis obtained (4-chloro-acetyl-l-11aphthyloxy) acetic acid. 1

STEP B.(d-BENZYLMERCAPTOACETYL-LNAPHTHYL OXY)ACETIC ACID By replacingthe [4-(y-chlor-obutyryl)-1-naphthyloxy] acetic acid and the thiophenolemployed in Example 37, Step B, by equivalent quantities of(4-chloroacetyl-1- naphthyloxy)acetic acid and benzylmercaptan,respectively, and following substantially the same procedure describedin Example 37, Step B, there is obtained (4-benzylcarcaptoacetyld-naphthyloxy)acetic acid.

EXAMPLE 38 [4- fi-triflaoromethylbutyryl) -1-naphthyl0xy] acetic acidAluminum chloride (0.28 mole) is added portionwise over 45 minutes to amixture of 0.093 mole of (l-naphthyloxy)acetic acid and 0.095 mole offi-trifluoromethylbutyryl chloride in 250 ml. of carbon disulfide cooledin an ice bath. The mixture is stirred at room temperature for 5 hoursand allowed to stand at room temperature for an additional 18 hours. Thereaction mixture then is worked up in substantially the same manner asdescribed in Example 8, Step B, to give[4-(fi-trifiuoromethylbutyryl)-l-naphthyloxy] acetic acid.

EXAMPLE 39 (4-phen0xyacetyl-1-naphthyl0xy)ace!ic acid A solution of (4chloroacetyl-l-naphthyloxy)acetic acid, prepared as described in Example37, Step A, (0.01 mole) and phenol (0.02 mole) in 50 ml. of water and 4ml. of 20% aqueous sodium hydroxide is heated on the steam bath for onehour, cooled and acidified with hydrochloric acid to give(4-phenoxyacetyl-l-naphthyloxy) acetic acid.

EXAMPLE 40 a-(4-butyryl-1-naphthyl0xy)isovaleric acid By followingsubstantially the same procedure described in Example I, Step D, butreplacing the 5hydroxy-1- butyronaphthone and the ethyl bromoacetatedescribed therein by equimolecular quantities of4-hydroxy-l-butyronaphtnone and ethyl a-bromoisovalerate, respectively,and following substantially the same procedure described in Step D ofExample 1, there is obtained a-(4-butyryl-1- uaphthyloxy)isovalericacid.

EXAMPLE 41 [4-(a-propylvaleryl)-1-naphthyloxy]acctic acid By replacingthe (Z-methyl-l-naphthyloxy)acetic acid and the butyryl chlorideemployed in Step B of Example 8 by equimolecular quantities ofl-naphthyloxyacetic acid and a-propylvaleryl chloride, respectively, andfollowing substantially the same procedure described in Example 8, StepB, there is obtained [4-(a-propylvaleryl)-1-naphthyloxy1acetic acid.

EXAMPLE 42 (3-butyryl-Z-naplzthyloxy)acetic acid STEPA.3-uETHOXY-2-BUTYRONAPHTHONE 3-methoxy-2-naphthoyl chloride (15.4 g.,0.07 mole) in 50 ml. of benzene is added dropwise to propyl cadmium STEPB.-3 HYDROXY-Z-BUTYRONAPHTHONE Aluminum chloride (10 g.) is added to asolution of 3- methoxy-2-butyronaphthone (5 g.) in 75 ml. of xylene at90 C. After refluxing for eight minutes the mixture is poured onto colddilute hydrochloric acid and extracted with ether, Concentration of theether gives 4 g. of 3- hydroxy-Z-butyronaphthone which, afterrecrystallization from hexane, melts at 83-855 C.

STEP C.(3-BUTYRYL-2-NAPHTHYLOXY)ACETIC ACID To a suspension of potassiumcarbonate g.) in 200 ml. of acetone is added 3-hydroxy-2-butyronaphthone(5.5 g., 0.025 mole) and ethyl bromoacetate (4.3 g., 0.025 mole). Themixture is refluxed for 17 hours, the inorganic salts filtered ofl andthe filtrate concentrated to an oil. The residual oil is suspended in100 ml. of a potassium hydroxide solution and heated at 100 C. for 0.5hour. The resulting solution is acidified with hydrochloric acid; asolid precipitates and the precipitate is then extracted with ether. Theether solution is extracted with aqueous sodium bicarbonate and thealkaline extract acidified with hydrochloric acid to yield a solid.After recrystallization from benzene 4.5 g of(3-butyryl2-naphthyloxy)acetic acid melting at 141142 C. is obtained.

Analysis for: C H O .Calt:ulated: C, 70.57; H, 5.92. Found: C, 70.87; H,6.22.

EXAMPLE 43 (Z-bzziyryZ-Imaphfhyloxy)acetic acid1-hydroxy-2-butyronaphthone (21.4 g., 0.1 mole) and ethyl bromoacetate(17 g., 0.1 mole) are added to a suspension of potassium carbonate (40g.) in 1 liter of acetone. The mixture is refluxed for 2 hours, stirredfor 17 hours and then refluxed an additional 2 hours. The inorganicsalts which separate out are then removed by filtration and the filtrateis concentrated under reduced pressure to yield an oil. The oil issuspended in 500 ml, of a 10% aqueous sodium hydroxide solution andheated 1.5 hours at 100 C. The solution is cooled, acidified withhydrochloric acid and extracted with ether. The ether solution is thenextracted with sodium bicarbonate and the basic extract acidified withhydrochloric acid to yield an oil, which is subsequently extracted withether. The ether solution is concentrated to give 14.5 g. of(2-butyryl-1- naphthyloxy)acetic acid; the cyclohexylamine salt of whichmelts at ll9l20 C.

Analysis for: C H O 'C H N.CalCulated: C, H, 7.87; N, 3.77. Found: C,71.02; H, 8.05; N, 3.67.

EXAMPLE 44 (1-butyryl-2-naplzthyl0xy)aceiic acid2-hydroxy-1butyronaphthone (6.4 g., 0.03 mole) is added to a solution ofsodium ethoxide (0.036 mole) in 100 ml. of ethanol. Ethyl bromoacetate(6.0 g., 0.036 mole) is added and the reaction mixture is refluxed 4hours. The solvent is then removed and 250 ml. of water is added to theresidue. The aqueous solution is extracted with ether and the etherextract concentrated to yield ethyl (l-butyryl-Z-naphthyloxy)acetatewhich is evaporatively distilled to give 5.5 g. of product, B.P. l90-200C./0.6

Ethyl (l-butyryl-Z-naphthyloxy)acetate (4 g.) is added to 50 ml. of a20% sodium hydroxide solution which is heated 1 hour at 100 C. Thesolution is cooled, acidified with hydrochloric acid and the productextracted with ether. The ether solution is then extracted with aqueoussodium bicarbonate and the resulting alkaline extract is acidified withhydrochloric acid to yield (l-butyryl-Z- naphthyloxy)acetic acid. Afterrecrystallization from n-butyl chloride there is obtained 2.3 g. of(1-butyryl-2- naphthyloxy)acetic acid melting at 102-1035 C.

Analysis for: C H O .Calculated: C, 70.57; H, 5.92. Found: C, 10.71; H,6. 09.

EXAMPLE 45 (8-bufyiyl-1-naphthyl0xy acetic acid STEPA.S-METHOXY-l-BUTYRONAPHTHONE Thionyl chloride is added dropwise to asolution of 8-methoxy-1-naphthoic acid (4 g., 0.02 mole) in 40 ml. ofether. After refluxing 45 minutes, the solvent and excess thionylchloride are removed under reduced pressure to yield 3.3 g. of crudeacid chloride which, after recrystallization from cyclohexane, melts at5964 C. The crude S-methoxy-l-naphthoyl chloride (3.3 g., 0.015 mole) isthen dissolved in 25 ml. of benzene and added to suspension of arefluxing solution of propyl cadmium (0.025 mole) in 40 ml. of benzene.The suspension is refluxed 45 minutes, stirred at room temperature for45 minutes and poured onto cold, dilute sulfuric acid. The mixture isextracted with ether, and the ethereal solution concentrated to an oil.After evaporative distillation at 180 C./ 1 mm, 1.8 g. of pureS-methoxy-l-butyronaphthone is obtained.

Analysis for: C H O .Calculated: C, 78.92; H, 7.06. Found: C, 78.99; H,7.34.

STEP B.8-HYDROXY-l-BUTYRONAPHTHONE To a solution of8-methoxy-l-butyronaphthone (2.1 g., 0.01 mole) in methylene chlorideml.), which has been cooled to 80 C., is added boron tribromide (3 g.,0.02 mole). The reaction mixture is allowed to warm to 25 C. and pouredinto water. The organic layer is separated and concentrated to yield8-hydroxy-l-butyronaphthone.

STEP C.(S-BUTYRYL-LNAPHTHYLOXY) ACETIC ACID By substituting8-hydroxy-l-butyronaphthone for the 3-hydroxy-2-butyronaphthone ofExample 42, Step C, and following substantially the procedure describedtherein, the compound (8-butyryl-1-naphthyloxy)acetic acid is prepared.

EXAMPLE 46 2- (4-butyiyl-1-naphthyloxy -2-methylpr0pi0nic acid4-hydroxy-l-butyronaphthone (20.8 g., 0.0972 mole) is dissolved in ml.of acetone and protected from oxidation by an atmosphere of nitrogen. Tothis solution 19.4 g. (0.485 mole) of sodium hydroxide is added over a15 minute period and the mixture is heated to reflux. Chloroform (14.5g., 0.122 mole) is added over 15 minutes and then the reaction isstirred and heated for 5 hours. The organic solvents are removed byevaporation under vacuum and the residue is dissolved in a mixture of300 ml. of Water and ml. of ether. The layers are separated and theether solution is extracted once with 100 ml. of 0.5 N sodium hydroxide.The aqueous alkaline solution thus obtained is then acidified withhydrochloric acid and extracted with ether. The'ether extract is thenextracted three times with saturated sodium carbonate solution and theaqueous portions are combined. Acidification of the combined sodiumcarbonate solutions yields 25.4 g. (87%) of solid2-(4-butyryl-l-naphthyloxy)-2-methylpropionic acid. Recrystallizationfrom butyl chloride gives material which melts at 142143 C.

Analysis for: C H O .-Calculated: C, 71.98; H, 6.71. Found: C, 71.94; H,6.55.

. 2? EXAMPLE 47 2-(S-butyryZ-Z-naphtlzyloxy)-2-metlzylpropi0nic acid Bysubstituting 6-hydroxy-l-butyronaphthone for the4-hydroxy-l-butyronaphthone of Example 46, and following substantiallythe same procedure described therein, the compound2-(S-butyryl-Z-naphthyloxy)-2-methyl. propionic acid is prepared.

Following the acidification of the sodium carbonate solution an 84.4%yield of solid is obtained. Recrystallization from butyl chloride yieldspure 2-(5-butyryl-2- naphthylo'xy)-2-methylpropionic acid melting at119- 120 C.

Analysis for: C H O .-Calculated: C, 71.98; H, 6.71. Found: C, 71.98; H,6.69.

EXAMPLE 48 2- 6-pr0pz'0nyZ-2-naphthyloxy -2-metlzylpr0pi0nic acid Bysubstituting 6-hydroxy-Z-propionaphthone for the4-hydroxy-l-butyronaphthone of Example 46, and following substantiallythe same procedure described therein, the compound 2-(6 propionyl 2naphthyloxy) 2-methylpropionic acid is prepared.

Acidification of the sodium carbonate extract gives an 86% yield ofsolid product. Recrystallization from toluene yields pure 2-(6 propionyl2 naphthyloxy)-2-methylpropionic acid which melts at 131132.5 C.

Analysis for: C H O .-Calculated: C, 71.31; H, 6.34. Found: C, 71.30; H,6.32.

EXAMPLE 49 (6-ba2yryl-2-naphthyl0xy)acetic acid Aluminum chloride (49.5g., 0.375 mole) is added to a Well-Stirred mixture of carbon disulfide(500 ml.), (2-naphthyloxy)acetic acid (25.0 g., 0.125 mole), nbutyryichloride (15.0 g., 0.138 mole) and dimethylformamide (15 ml.) at 3 C.After all the aluminum chloride has been added, the mixture is allowedto stand at room temperature for one hour and it is then heated underreflux for three hours. The reaction is cooled and 500 ml. of a mixtureof ice and 1 N hydrochloric acid is added and the mixture stirred fortwo hours. The resulting white solid which is in suspension is collectedby filtration and washed with water. After purification byrecrystallization from dipropyl ketone, 24 g. of pure (6-butyryl-2-naphthyloxy)acetic acid is obtained, M.P. 168-170 C.

Analysis for: C H O .-Calculated: C, 70.57; H, 5.92. Found: C, 70.28; H,6.02.

EXAMPLE 5 0 [4-(2-methylbutyryl -naphthyl0xy] acetic acid Bysubstituting u-methylbutyryl chloride for the a-ethylbutyryl chloride ofExample 12, and following substantially the same procedure describedtherein, the compound [4-(2-methylbutyryl) 1 naphthyloxy1acetic acid isprepared. Crystallization from a mixture of n-butyl chloride and hexaneyields pure material melting at 95.597 C.

It will be apparent from the foregoing description that the alkanoylsubstituted naphthyloxy-carboxylic acids of this invention constitute avaluable class of compounds which have not been prepared heretofore. Oneskilled in the art Will also appreciate that the processes disclosed inthe above examples are merely illustrative and are capable of widevariation and modification without departing from the spirit of thisinvention.

28 What is claimed is: 1. A compound of the formula:

wherein B is a member selected from the group consisting of alkylene,alkarylene and arylene; R is a member selected from the group consistingof alkyl containing from one to six carbon atoms, trihalomethylsubstituted alkyl, cycloalkyl, mononuclear aralkyl, mononuclear aryloxy,mononuclear arylthioalkyl, mononuclear aralkylthio and carboxyalkyl; Rand R each represents a member selected from the group consistingofhydrogen, lower alkyl and, taken together, the R and R radicals may bejoined to form a cycloalkyl ring containing from five to six nuclearcarbon atoms; X is a member selected from the group consisting ofhydroxy, lower alkoxy and amido; and X and X each represents a memberselected from the group consisting of hydrogen, halogen and lower alkyl.

2. A compound of the formula:

wherein R is lower a kyl and n is an integer having a value of 15.

3. A compound of the formula:

wherein R is lower alkyl; X is halogen; m is an integer having a valueof 12; and n is an integer having a value of 1-5.

4. A compound of the formula:

wherein R is lower alkyl; X is lower alkyl; m is an integer having avalue of l-2; and n is an integer having a value of 1-5.

5. (2-chloro-4-butyryl-l-naphthyloxy)acetic acid.

6. (4-butyryl-1-naphthyloxy)acetic acid.

7. (4-butyryl-2-naphthyloxy)acetic acid.

8. (5-ch1oro-4-butyryl-1-naphthy-loxy)acetic acid.

9. (4-butyryl-3-methy1-1-naphthyloxy)acetic acid.

10. (4-butyryl-5-methy1-l-naphthyloxy)acetic acid.

11. (6-methy1-4-butyryl-l-naphthyloxy)acetic acid.

References Cited Thomas, Aluminum Chloride in Organic Chemistry (1941pp. 271-273; 363-364.

Elseviers Ency. Org. Chem., v01. 12B, Naphthalene Hydroxy Compounds, p.1201.

LORRAINE A. WEINBERGER, Primary Examiner.

S. B. WILLIAMS, D. E. STENZEL, Assistant Examiners.

1. A COMPOUND OF THE FORMULA: